There are dynamic bidirectional interactions between the immune and central nervous systems that affect behavior and mental health. The current proposal joins a growing literature investigating the role of immune cells in the brain. The focus here is on mast cells because of their unique granular and mobile characteristics and their ability to release neuroactive and neurotrophic mediators. Mast cells in the brain have a direct effect on the regulation of anxiety (Nautiyal et al, 2008). Both genetic and pharmacological models (using mast cell-deficient mice and a drug that blocks mast cell degranulation, respectively) of mast cell loss-of-function show that a lack of mast cells or their products result in increased anxiety-like behavior, with no effects on homecage behavior or sensory responsiveness. This proposal explores the mechanism for mast cell modulation of anxiety. The likely site of mast cell impact on the limbic system is the hippocampus. Hippocampal signaling regulates depression and anxiety, brain mast cells are located within and near the hippocampus, and a number of mast cell mediators can affect hippocampal physiology. For example, serotonin (a major mast cell mediator) in the hippocampus influences neurogenesis in the dentate gyrus and results in changes in anxiety and depression. Additionally, increases in neurogenesis are thought to be responsible for the effects of serotonin acting (SSRI) anti-depressants on depressive and anxious behaviors. Preliminary data shows that mast cell deficient sash-/- mice have decreased cell proliferation and survival in the dentate gyrus suggesting that mast cells contribute to the maintenance of hippocampal neurogenesis. Experiments here will extend this research using a pharmacological model of mast cell loss-of-function and will also explore the behavioral consequences of a lack of mast cell mediated neurogenesis. Subsequent experiments will focus on delineating which mast cell mediators affect cell proliferation. This will include in vivo experiments assessing mast cell contribution to the hippocampal milieu, as well as in vitro experiments exploring the direct mechanisms of mast cell influence on neural stem cells. Finally, behavioral and histochemical experiments will assess mast cell influences on the efficacy of SSRI antidepressants. Relevance: Psychiatric diseases, like anxiety and depression, are correlated with abnormalities in the immune system, which in turn has recently become a focus of new treatments for the management of these disorders. The research proposed will explore how immune cells in the brain can impact mental health, potentially contributing to new pharmaceutical targets.